The present invention relates generally to methods and apparatus for treating or controlling medical, psychiatric or neurological disorders by application of modulating electrical signals to a selected nerve or nerve bundle of the patient, and more particularly to techniques for treating patients with sleep disorders by application of such signals to a cranial nerve, using an implantable neurostimulating device. Specifically, the invention is directed toward treating various sleep disorders, such as insomnia, hypersomnia, apnea, and narcolepsy, by selective modulation of vagus nerve electrical activity.
Sleep is not a uniform state, but rather involves several stages characterized by changes in the individual's EEG. Stage 1 sleep is drowsiness, in which the EEG displays a lower voltage, more mixed frequencies and deterioration of alpha rhythm relative to the EEG when the individual is awake, even when in a relaxed state. In stage 2, background activity similar to that of stage 1 is experienced, with bursts of slightly higher frequency "sleep spindles" and sporadic higher amplitude slow wave complexes. The third and fourth stages of sleep display increasing high amplitude slow wave activity. A separate sleep stage is one in which the individual undergoes rapid eye movements (REM) with lower voltage, higher frequency EEG and other characteristics similar to those which occur when the individual is awake, whereas the other four sleep stages are categorized as non-REM (NREM) sleep.
Normally, the extent to which NREM stages and REM sleep are experienced, as well as the sleep requirements of the individual, are largely age dependent. Adults typically pass in sequence through the four stages of NREM sleep, and may enter several spaced periods of REM sleep during the night. Adults usually require only six or seven hours of sleep, while infants require sleep during both day and night (normally 50% of the sleep time being spent in REM sleep), and the aged require less sleep than the adult and may experience no REM sleep.
The principal sleep disorders are central sleep apnea, insomnia and hypersomnia, and the syndromes thereof. Other sleep disorders include sleep walking and enuresis (nocturnal incontinence, or bed-wetting). The latter two disorders are primarily confined to children. Insomnia is a chronic inability to sleep or to remain asleep throughout the night, and is usually suffered as a result of various physical and/or physiologic factors, such as pain, discomfort, anxiety, depression, tension, and obstructive sleep apneas. Sleep apneas are characterized by brief episodes of respiratory arrest, which may occur many times during sleep and may be associated with obstruction of the upper airways, cessation of diaphragmatic movements and snoring. Hypersomnia is a condition in which the individual undergoes sleep of excessive depth or abnormal duration, usually caused by physiologic rather than physical factors and characterized by a state of confusion on awakening. Daytime hypersomnia, which may complicate sleep apnea, is commonly represented by the narcoleptic syndrome, characterized by sudden sleep attacks, cataplexy, sleep paralysis, and visual or auditory hallucinations at the onset of sleep.
Conventional treatment of insomnia typically involves hypnotics (drugs employed as sedatives), while treatment of narcolepsy and other syndromes of hypersomnia often utilizes stimulant drugs such as dextro- and laevo-amphetamine and methylphenidate. Unfortunately, however, treatment with drugs has not proved very effective and often results in undesirable side-effects.
It is a principal object of the present invention to apply techniques of selective modulation of the electrical activity of a cranial nerve, and particularly the vagus nerve, to treat and control at least the principal sleep disorders, including sleep apnea, insomnia, hypersomnia, narcolepsy, and syndromes thereof.
In addressing a therapy involving nerve stimulation to treat sleep disorders, notice should be taken of existing knowledge that most nerves in the human body are composed of thousands of fibers, having different sizes designated by groups A, B and C, carrying signals to and from the brain and other parts of the body. The vagus nerve, for example, may have approximately 100,000 fibers (axons) of the three different types, each of which carries such signals. Each axon of that nerve only conducts in one direction, in normal circumstances. The A and B fibers are myelinated, that is, they have a myelin sheath in the form of a substance largely composed of fat. On the other hand, the C fibers are unmyelinated.
Myelinated fibers are typically larger, have faster electrical conduction and much lower electrical stimulation thresholds than the unmyelinated fibers. Along with the relatively small amounts of electrical energy needed to stimulate the myelinated fibers, it is noteworthy that such fibers exhibit a particular strength-duration curve in response to a specific width and amplitude of stimulation pulse.
The A and B fibers are stimulated with relatively narrow pulse widths, from 50 to 200 microseconds (.mu.s), for example. A fibers exhibit slightly faster electrical conductivities than the B fibers, and slightly lower electrical stimulation thresholds. The C fibers are relatively much smaller, conduct electrical signals very slowly, and have high stimulation thresholds typically requiring wider pulse widths (e.g., 300-1000 .mu.s) and higher amplitudes for activation. Although the A and B fibers may be selectively stimulated without also stimulating the C fibers, the magnitude and width of the pulse required for stimulating the C fibers would also activate A and B fibers.
Although electrical stimulation of the nerve fiber typically activates neural signals in both directions (bidirectionally), selective unidirectional stimulation is achievable through the use of special nerve electrodes and stimulating waveforms. As noted above, each axon of the vagus nerve normally conducts in only one direction.
In a paper on the effects of vagal stimulation on experimentally induced seizures in rats (Epilepsia (1990) 31 (Supp 2): S7-S19), Woodbury has noted that the vagus nerve is composed of somatic and visceral afferents (i.e., inward conducting nerve fibers which convey impulses toward a nerve center such as the brain or spinal cord) and efferents (i.e., outward conducting nerve fibers which convey impulses to an effector to stimulate it and produce activity). The vast majority of vagal nerve fibers are C fibers, and a majority are visceral afferents having cell bodies lying in masses or ganglia in the neck. The central projections terminate, by and large, in the nucleus of the solitary tract which sends fibers to various regions of the brain (e.g, the hypothalamus, thalamus, and amygdala); others continue to the medial reticular formation of the medulla, the cerebellum, the nucleus cuneatus and other regions.
Woodbury further notes that stimulation of vagal nerve afferent fibers in animals evokes detectable changes of the EEG in all of these regions, and that the nature and extent of these EEG changes depends on the stimulation parameters. Chase, in Exp Neurol (1966) 16:36-49, had also observed that vagal activation can affect the EEG activity of certain parts of the brain. The applicants herein postulate that synchronization of the EEG may be produced when high frequency (&gt;70 Hz) weak stimuli activate only the myelinated (A and B) nerve fibers, and that desynchronization of the EEG occurs when intensity of the stimulus is increased to a level that activates the unmyelinated (C) nerve fibers. Woodbury also observes that vagal stimulation can produce widespread inhibitory effects on seizures and certain involuntary movements.
Extra-physiologic electrical stimulation of the vagus nerve has previously been proposed for treatment of epilepsy and various forms of involuntary movement disorders. Specifically, in U.S. Pat. No. 4,702,254 issued Oct. 27, 1987 to J. Zabara (referred to herein as "the '254 patent"), a method and implantable device are disclosed for alleviating or preventing epileptic seizures, characterized by abnormal neural discharge patterns of the brain. The '254 patent describes an implantable neurocybernetic prosthesis (NCP) which utilizes neurocybernetic spectral discrimination by tuning the external current of the NCP generator to the electrochemical properties of a specific group of inhibitory nerves that affect the reticular system of the brain. These nerves are embedded within a bundle of other nerves, and are selectively activated directly or indirectly by the tuning of the NCP to augment states of brain neural discharge to control convulsions or seizures. According to the patent, the spectral discrimination analysis dictates that certain electrical parameters of the NCP pulse generator be selected based on the electrochemical properties of the nerves desired to be activated. The patent further indicates that the optimum sites for application of the NCP generator output to produce the desired effects are the cranial nerves in general, and the vagus nerve in particular.
The NCP disclosed in the '254 patent may be activated either manually or automatically, to provide treatment for the duration of the seizure. Manual activation is performed when the patient experiences the aura at onset of the seizure. Alternatively, automatic activation may be triggered upon detection of instantaneous changes in certain state parameters immediately preceding or at onset of a seizure. Additionally, a prophylactic or preventive mode may be employed in which the NCP is activated periodically to reduce the occurrence and/or the intensity of the seizures. The NCP stimulator of the '254 patent is implanted in the patient's chest and is connected to electrodes installed at the selected point of signal application at the nerve site with the more negative electrode situated closer to the brain and the positive electrode further from the brain, along the vagus nerve.
There is substantial evidence to indicate that sleep is modulated by brain stem centers. Because these centers receive input from the vagus nerve, their activity can be affected by vagal stimulation. The following are some scientific papers of interest on this subject. In Exp. Brain Res. Suppl. (1984) 8:3-18, Sakai describes synchronized sleep (NREM) and desynchronized sleep (REM) and the brain centers which control them in the cat. Puizillout et al. showed, in Brain Res. (1976) 11:181-184, that vagal stimulation may increase the number or duration of REM episodes, the total amount of REM being found constant; and, in Electroencephalog. Clin. Neurophysiol. (1977) 42:552-563, that sleep cycles may be induced by stimulation of the vagus nerve. Another Puizillout et al. group reviewed, in Exp. Brain Res. Suppl. (1984) 8:20-38, literature on the evidence for involvement of the nucleus of the solitary tract and vagal afferents in modulation of sleep cycles. In Brain Res. Bull. (1985) 15:437-441, Juhasz et al. showed that vagal stimulation directly affects reticular and ventro-posterior-medial nuclei of the cat thalamus; neural activity recorded depended on stimulus parameters, sleep state and site of recording.